The principal objectives of the research are to determine the structure of fibers of hemoglobin S formed in sickle cell anemia and related sickle cell diseases which involve interaction of sickle cell hemoglobin S with other mutant hemoglobins giving rise to pathological states. Investigations will center on: 1) Electron microscopic study of negatively stained fibers formed in red cells of individuals homozygous for hemoglobin S and heterozygous for Hn S and other mutant sickling hemoglobins. 2) Freeze fracture of whole sickle cells. 3) "Low dose" microscopy of large two-dimensional arrays of unstained sickle fibers. 4) Analysis of the electron micrographs obtained by the above methods by recently developed Fourier methods will be carried out to determine the three dimensional mass distribution and orientation of individual molecules within the hemoglobin fiber. 5) In parallel with electron microscopic studies, methods will be devised to obtain very well oriented fibers of sickle hemoglobin suitable for X-ray diffraction. With the availability of the crystal structure of hemoglobin and a knowledge of the position and orientation of the molecules in fibers derived from the above studies, it will be possible to define those amino acid residues involved in the contacts between hemoglobin molecules comprising the sickle cell fiber. Once the sites of interaction between molecules have been identified, molecules which can interact with these sites, compete with, and inhibit the self-aggregation of hemoglobin S will be designed. Such studies would thus provide much needed information on the mode of aggregation of hemoglobin S and indicate strategies in the design of anti-sickling agents of therapeutic value.